1. Field of the Invention
This invention relates generally to the transdermal delivery of medicament and, more specifically, to an apparatus for the iontophoretic and ultrasonic delivery of medication across the skin or other biological tissue.
2. Prior Art
Iontophoresis has existed for several centuries as a means for applying medication locally through a patient's skin and for delivering medicaments to the eyes and ears. The application of an electric field to the skin is known to greatly enhance the skin's permeability to various ionic agents. The use of iontophoretic techniques has obviated the need for hypodermic injection of certain medicaments, thereby eliminating the concomitant problems of trauma, pain and risk of infection to the patient.
Iontophoresis involves the application of an electromotive force to drive or repel oppositely charged ions through the dermal layers into the area to be treated; either into the surrounding tissues for localized treatment or into the circulatory system for systemic treatment. Positively charged ions are driven into the skin at the anode while negatively charged ions are driven into the skin at the cathode. Studies have shown increased skin penetration of drugs at anodic or cathodic electrodes regardless of the predominant molecular ionic charge. This effect is mediated by polarization and osmotic effects. Regardless of the electrical charge on the medicament employed, two electrodes are used in conjunction with the patient's skin to form a closed circuit to promote the penetration or absorption of the medicament through the skin underlying the working electrode.
One readily observed benefit of transdermal iontophoretic drug delivery is the increased efficacy of the drugs delivered in this fashion. U.S. Pat. No. 5,160,316, to the instant inventor, incorporated herein by reference, describes the use of a multichannel dispersive eleotrode. Each channel is driven by separate electronic circuits to assure wide dispersion and enhanced penetration of medicament. Such wide field electrodes not only can cover a wide area of body without succumbing to "tunneling effects" but provide sufficient skin penetration to function as a systemic drug delivery system. A co-pending patent application by the present inventor describes a user-friendly iontophoretic system to deliver nicotine as a device to help people quit smoking or, alternatively, to provide established smokers with a noncarcinogenic smokeless cigarette.
Prior art iontophoretic systems have not proved useful for delivery of insulin via the transdermal route. Such a system would be extremely important in the management of diabetic patients and in decreasing the long term complications of diabetes. The patient would be freed from multiple injections of insulin and strict dietary controls which are the mainstay of current therapy of Diabetes Mellitus. It is believed that improved control of intraday glucose fluctuations will significantly decrease the long term complications of diabetes such as blindness and renal failure. Improved control of diabetic pregnancy and children will enhance and prolong life. An iontophoretic insulin delivery system must employ an electrode that avoids current flowing along the path of least resistance into a lesion or skin rupture, resulting in a localized burn.
The foregoing problems are solved by the present invention by providing an improved iontophoretic medicament applicator and combining this iontophoretic dispersion electrode with ultrasonic enhancement of penetration. Ultrasonic fields can readily be generated in the skin underlying an electrode by means of oscillator circuits applying a high frequency voltage waveform to piezoelectric crystals (i.e. quartz) mounted on the dispersive application electrode. It is the nature of piezoelectric crystals to convert electrical oscillations to vibration by means of crystal lattice elongation. Numerous materials such as ceramics (barium titanate), and variations of lead zicornate-lead titanate exhibit good piezoelectric properties and can be mounted on such an electrode. A preferred manufacture of a pliant contouring electrode producing low energy ultrasonic fields utilizes a sheet of Kynar.TM. polyvinelidene fluoride film that exhibits piezoelectric properties when energized yet retains pliability, stability and absence of toxicity. Such laminates of piezo film are known in the art and have already been manufactured. A bending motion (analogous to bimetallic action of thermostats) can be generated in response to an applied voltage where the top film expands while the bottom contracts. Alternating voltage creates film vibration in phase with applied oscillator output. For higher energy applications multiple mounted piezoelectric crystals or ceramic elements on a flexible iontophoretic sheet will be preferable.